Effect of gastrin heptadecapeptide (G17) on oesophageal contractions in patients with diffuse oesophageal spasm.

An intravenous bolus of pentagastrin significantly increased the amplitude and duration of oesophageal body contractions in seven patients with diffuse oesophageal spasm (DES) when compared with five normal subjects (P greater than 0.05). In order to determine whether this stimulation also occurred at physiological gastrin concentrations, the effect of an intravenous infusion of gastrin heptadecapeptide (G17), 25 pmol/kg-h, on oesophageal contractions was studied in DES patients. G17 had no significant effect on the amplitude and duration of oesophageal contractions compared with a saline control. This dose of G17 was near the D50 for gastric acid secretion and produced a rise in serum gastrin concentration comparable with a meal. G17 infusions at doses of 100 and 200 pmol/kg-h increased the amplitude and duration of oesophageal contractions, but the corresponding serum gastrin concentrations were higher than postprandial levels. Thus, endogenous fluctuations in serum gastrin heptadecapeptide, alone, are unlikely to alter oesophageal contractions in DES patients.     

Usefulness of fasting plasma glucose to predict mortality or coronary heart disease in persons > or = 60 years of age without diabetes mellitus or in those with undiagnosed diabetes mellitus (from The Dubbo Study)

The role of fasting plasma glucose (FPG) levels below diabetes "thresholds" in predicting mortality or coronary heart disease (CHD) is unclear. This study examines whether FPG predicts mortality or CHD in subjects without diabetes (historical or undiagnosed) or in those with undiagnosed diabetes (or lesser degrees of glucose intolerance). We have analyzed all-causes mortality and CHD incidence from a 16-year follow-up in a cohort of Australian senior citizens, 60 years and older, first examined in 1988-89. Diabetes was defined on historical grounds or by use of medication; undiagnosed diabetics were those without history but with FPG >124 mg/dl. Hazard ratio and 95% confidence intervals of the specified outcomes were obtained from Cox models, with FPG being entered as a continuous variable. Mortality and CHD incidence rates in subjects with previous cardiovascular disease (CVD) and diabetes were substantially higher than in nondiabetics, but CHD rates were disproportionately higher in diabetic women. FPG did not significantly predict any outcome in men in the absence of diabetes. In women, FPG was a significant predictor of death (hazard ratio = 1.30, 95% confidence interval 1.09 to 1.56) and CHD (hazard ratio 1.24, confidence interval 1.02 to 1.51) in the cohort, which included previous CVD but excluded all diabetes. In women with undiagnosed diabetes, FPG predicted death independently of previous CVD presence but did not predict CHD. In conclusion, FPG in the range of 95 to 108 mg/dl in a nondiabetic woman is still of prognostic importance for survival or CHD if she has previous CVD, whereas FPG is of prognostic importance for survival if she has undiagnosed diabetes. No similar findings were made in men.     

The hypertensive lower esophageal sphincter

Controversy exists as to whether the hypertensive lower esophageal sphincter (HLES) represents a clinical motility disorder of the esophagus or is merely the right-sided expression of a normal distribution curve. In the present study we describe 16 patients with HLES, defined as a lower esophageal sphincter (LES) pressure of 40 mm Hg (mean +3sd of controls) with normal peristalsis. All of the patients suffered from chest pain and nine from dysphagia. Delayed bolus transit at the gastroesophageal junction was demonstrated in four patients by radiography. Manometric studies showed that during swallowing the LES residual pressures were significantly greater (9.2±5.0 mm Hg) than observed in normal controls (1.8±2.2 mmHg) (mean±1sd). However, the percent LES relaxation in patients did not differ significantly from controls. Clinical improvement was associated with pharmacological or mechanical reduction of resting LES pressure with an accompanying fall in the nadir pressure. These observations suggest that HLES may have clinical and pathophysiological significance and that evidence for the entity should be sought during manometric studies in the clinical laboratory.     

Associations between Bodyweight and Clinical Outcome in Patients Post-Fontan Procedure: A Systematic Review

Background: Patients born with a single ventricle circulation commonly experience growth failure in early life, which is associated with adverse outcomes in infancy. However, associations between bodyweight or weight trajectory and clinical outcome post-Fontan procedure are yet to be determined. Methods: On the 1st of July 2021, a systematic review was performed in MEDLINE, EMBASE, the Cochrane Library, and Scopus of studies of patients with clinical outcome data post-Fontan procedure and association with bodyweight. Quality of studies was evaluated by Newcastle–Ottawa scale for cohort studies and Joanna Briggs Institute tool for cross-sectional studies. Results: Of 527 studies that underwent title and abstract screening, 15 were selected for final review. An increased risk of adverse post-Fontan outcomes was found for low weight patients, consistent with findings in infants. Whilst there is some evidence to suggest increased mortality in overweight adult patients, studies are conflicting as to whether overweight status is associated with increased heart failure. Increased BMI is associated with diminished exercise capacity and deceased physiological functioning. Negative weight trajectory is associated with adverse outcomes in the peri-Fontan period, whereas a positive weight trajectory is associated with increased Fontan failure in adulthood. Abnormal BMI (high or low) is associated with increased heart failure and poorer performance in quality-of-life scores. Conclusions: Bodyweight is a modifiable risk factor for poor clinical outcome in patients with a single ventricle circulation. Recognizing associations between bodyweight and Fontan pathophysiology may help to define patient-centered exercise and diet interventions that minimize patient morbidity and mortality.     

Sleep and nocturnal acid reflux in normal subjects and patients with reflux oesophagitis.

Nocturnal gastro-oesophageal reflux may be important in the pathogenesis of reflux oesophagitis. This study aimed to determine whether: (1) gastro-oesophageal reflux occurs during sleep in patients with reflux oesophagitis and, if so, to explore the mechanism, and (2) the sleep pattern of patients with oesophagitis is different from that of control subjects. After a standard evening meal, simultaneous manometric, oesophageal pH, and polysomnographic recordings were obtained in 11 patients with endoscopic oesophagitis and 11 control subjects. Patients with gastrooesophageal reflux disease had significantly more total reflux episodes throughout the nocturnal monitoring period than control subjects (105 v 6). Ninety two of 105 episodes of gastro-oesophageal reflux in patients occurred during the awake state and 10 during sleep stage II. A number of reflux episodes occurred during brief periods of arousal from the various sleep stages. Of the 105 reflux events recorded in patients, 42 were induced by transient lower oesophageal sphincter relaxation, 20 by stress reflux, 22 by free reflux mechanisms, and in 21 the mechanism was unclear. The sleep pattern and the time spent in each sleep stage was not different between the two groups. It is concluded that the awake state is crucial for the occurrence of nocturnal reflux episodes in normal subjects as well as in patients with reflux oesophagitis and that the difference between the frequency of gastro-oesophageal reflux between normal subjects and patients cannot be explained by different sleep patterns.     

Treatment of gastroparesis with electrical stimulation

Electrically stimulating the stomach to treat gastroparesis has been proposed by investigators for decades. With the development of techniques of implantable pacing devices and electrodes and promising preliminary results in chronic pacing studies, gastric electrical stimulation (GES) has received increasing attention recently among researchers and clinicians. A number of studies have been performed to investigate the effects of GES on gastric motility, gastric emptying, and gastrointestinal symptoms in both dogs and humans. Based on the frequency of the electrical stimulus used for chronic treatment of gastroparesis, gastric electrical stimulation can be classified into low-frequency stimulation (LFS) and high-frequency stimulation (HFS). Although some of the results are still controversial, the majority of these studies seem to indicate that LFS is able to normalize gastric dysrhythmias and entrain gastric slow waves and accelerate gastric emptying. On the other hand, HFS has no effect on gastric emptying but is able to significantly reduce symptoms of nausea and vomiting in gastroparetic patients. GES has provided an exciting new advance in the treatment of gastroparesis and management of upper gastrointestinal symptoms. This paper will review the available studies of GES in the treatment of gastroparesis and current status of this field.     

Combined signaling through interleukin-7 receptors and flt3 but not c- kit potently and selectively promotes B-cell commitment and differentiation from uncommitted murine bone marrow progenitor cells

Multiple cytokines can synergize to stimulate the in vitro proliferation and exclusive myeloid differentiation of multipotent bone marrow progenitor cells. The ligand for c-kit (stem cell factor [SCF]) plays a key role in stimulating myeloid and erythroid cell production of primitive hematopoietic progenitors. SCF in combination with interleukin-7 (IL-7) can also stimulate the combined myeloid and B-cell differentiation of uncommitted hematopoietic progenitor cells as well as the growth of early B-cell progenitor cells, although the involvement of c-kit in early B lymphopoiesis remains controversial. In the present study, the flt3-ligand (FL), which, in combination with other cytokines, has overlapping activities with SCF on myeloid cell production from uncommitted progenitors, was investigated for its ability to induce selective stroma-independent B-cell commitment from uncommitted Lin-Sca-1+ bone marrow progenitor cells. IL-7 alone did not induce any clonal growth and FL alone gave rise to a few clusters (< 50 cells) but no colonies (> 50 cells), whereas the combined stimulation with FL and IL-7 resulted in clonal growth of 10% of Lin-Sca-1+ bone marrow cells. After 12 days of incubation of Lin-Sca-1+ cells in FL + IL-7, an almost 400-fold increase in cell production was observed. Phenotyping showed that greater than 99% of the cells produced were of the B-cell lineage, in that they expressed B220, but not cell surface markers specific for myeloid, erythroid, or T-cell lineages. Furthermore, the cells did not express cytoplasmic mu-heavy chain (cmu) or surface IgM, but were positive for CD24 (heat stable antigen [HSA]) and CD43 (leukosialin), suggesting that the cells produced were blocked at a late pro-B-cell stage. Interestingly, although all FL + IL-7- responsive Lin-Sca-1+ progenitor cells and the resulting pro-B cells expressed c-kit, FL + IL-7 was much more potent (62-fold) than SCF + IL- 7 in stimulating production of cells of the B-cell lineage. In addition, whereas FL + IL-7 selectively stimulated the production of pro-B cells, SCF + IL-7 predominantly stimulated the production of mature granulocytes. Replating studies showed that FL + IL-7-responsive Lin-Sca-1+ progenitors were not committed to the B-cell lineage, because after 2 days of incubation in FL + IL-7, 80% of the progenitors retained a myeloid potential. As much as 27% of the FL + IL-7- responsive progenitors remained uncommitted after 7 days of incubation, but all had committed to the B-cell lineage after 10 days of incubation in FL + IL-7. These results show that FL much more potently and selectively than SCF synergizes with IL-7 to enhance B-cell commitment and development from uncommitted progenitor cells.     

The activation-induced decrease in the platelet surface expression of the glycoprotein Ib-IX complex is reversible

Thrombin decreases the platelet surface expression of the glycoprotein (GP) Ib-IX complex. To determine whether this effect is reversible, flow cytometric studies were performed with GPIb-IX-specific monoclonal antibodies. In both whole blood and washed platelet systems, incubation of platelets with thrombin or a combination of adenosine diphosphate and epinephrine resulted in a maximal decrease of the platelet surface expression of GPIb-IX within 5 minutes, after which there was a time- dependent return of the platelet surface GPIb-IX complex, which was maximal by 60 minutes. Exposure of the same platelets to additional exogenous thrombin resulted in a second decrease in platelet surface GPIb-IX, followed by a second reconstitution of platelet surface GPIb- IX. Throughout these experiments there was no measurable release from the platelets of glycocalicin (a proteolytic fragment of GPIb). Experiments in which platelets were preincubated with a biotinylated GPIb-specific MoAb showed that the GPIb molecules that returned to the platelet surface were the same molecules that had been translocated to the intraplatelet pool. The GPIb molecules that returned to the platelet surface were functionally competent to bind von Willebrand factor, as determined by ristocetin-induced platelet agglutination and ristocetin-induced binding of exogenous von Willebrand factor. Inhibitors of protein kinase C and myosin light-chain kinase enhanced the reexpression of platelet surface GPIb. In summary, the activation- induced decrease in the platelet surface expression of the GPIb-IX complex is reversible. Inactivation of protein kinase C and myosin light-chain kinase are important mechanisms in the reexpression of the platelet surface GPIb-IX complex.     

Peripheral blood mononuclear cell expression of toll-like receptors and relation to cytokine levels in cirrhosis

Activation of macrophages by endotoxin is assumed responsible for increased circulating tumor necrosis factor alpha (TNF-alpha) and soluble TNF receptor (sTNFR) levels in cirrhosis. Relevant to this is expression of Toll-like receptor (TLR) 4 and TLR2, which is critically involved in production of TNF-alpha in response to endotoxin and Gram-positive microbial stimuli, respectively. The first studies on this in cirrhosis are reported here. In 36 cirrhotic patients and 32 controls, we measured (1) circulating endotoxin, TNF-alpha, and sTNFR levels; (2) peripheral blood mononuclear cell (PBMC) expression of TLR4 and TLR2, and (3) in vitro TNF-alpha production by PBMCs stimulated with endotoxin or Staphylococcus aureus enterotoxin B (SEB). PBMC expression of TLR2, circulating TNF-alpha levels, and in vitro TNF-alpha production were reassessed after supplementation with a synbiotic regimen known to increase intestinal levels of Gram-positive bacteria. Endotoxin, TNF-alpha, and sTNFR levels were significantly increased in cirrhosis. Endotoxin levels did not correlate significantly with other parameters. PBMC expression of TLR2 but not TLR4 was significantly up-regulated in cirrhosis and correlated significantly with serum TNF-alpha and sTNFR levels. In vitro TNF-alpha production by PBMCs stimulated by SEB was significantly blunted. Supplementation with the synbiotic regimen resulted in significant up-regulation of PBMC expression of TLR2. Serum TNF-alpha levels were further increased and in vitro TNF-alpha production further reduced in most patients. In conclusion, up-regulation of PBMC expression of TLR2 but not TLR4 occurs in cirrhosis, which implies, contrary to previous assumptions, an important stimulatory role for Gram-positive microbial components but not endotoxin. TLR2 likely contributes to increased circulating TNF-alpha and sTNFR levels in cirrhosis.     

"Segmental Aperistalsis" of the Esophagus: A Cause of Chest Pain and Dysphagia

Although some patients with chest pain and dysphagia have manometric evidence of classic esophageal motor disorders, other patients with these symptoms may have only nonspecific findings of unknown importance. We describe five patients with chest pain and dysphagia in whom esophageal manometry showed a segment of esophagus with an increased frequency of simultaneous contractions associated with normal motility in the more proximal and distal esophagus. All patients had corresponding segmental abnormalities on video-esophagograms augmented with a solid holus; in four patients, the solid bolus caused reproduction of symptoms during the esophagography. We conclude that "segmental aperistalsis" may cause chest pain and dysphagia, and that the diagnosis may be made by careful manometric analysis of the entire esophagus, complemented by esophagography with a solid bolus.